胰腺导管腺癌
HMGB1
癌症研究
医学
腺癌
胰腺癌
内科学
癌症
受体
作者
Li Ge,Cheng‐Yu Liao,Jiangzhi Chen,Zuwei Wang,Shun‐Cang Zhu,Jianlin Lai,Qiaowei Li,Yinhao Chen,Dihan Wu,Jianbo Li,Yi Huang,Yifeng Tian,Yanling Chen,Shi Chen
标识
DOI:10.1002/advs.202308208
摘要
Abstract Induction of ferroptosis can inhibit cancer cells in vitro, however, the role of ferroptosis in treatment in vivo is controversial. The immunosuppressive cells activated by the ferroptotic tumor cells can promote the growth of residual tumor cells, hindering the application of ferroptosis stimulation in tumor treatment. In this study, a new strategy is aimed to be identified for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma (PDAC) and simultaneously stimulating antitumor immune responses. Toward this, several molecular and biochemical experiments are performed using patient‐derived organoid models and a KPC mouse model ( LSL ‐ Kras G12D /+ , LSL‐Trp53 R172H/+ , Pdx‐1‐Cre ). It is observed that the inhibition of macrophage‐capping protein (MCP) suppressed the ubiquitin fold modifier (UFM)ylation of pirin (PIR), a newly identified substrate of UFM1, thereby decreasing the transcription of GPX4 , a marker of ferroptosis, and promoting the cytoplasmic transportation of HMGB1, a damage‐associated molecular pattern. GPX4 deficiency triggered ferroptosis, and the pre‐accumulated cytosolic HMGB1 is released rapidly. This altered release pattern of HMGB1 facilitated the pro‐inflammatory M1‐like polarization of macrophages. Thus, therapeutic inhibition of MCP yielded dual antitumor effects by stimulating ferroptosis and activating antitumor pro‐inflammatory M1‐like macrophages. The nanosystem developed for specifically silencing MCP is a promising tool for treating PDAC.
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